SUMMARY Ionizing Radiation (IR) induces p53-dependent and p53-independent apoptosis. Understanding p53-dependent apoptosis has benefited immensely from studies in mammalian cells that identified biochemical activities and genetic analysis in model organisms such as C. elegans and Drosophila that identified genes responsible for the activities. In contrast, IR- induced p53-independent apoptosis lacked a genetic model and remains poorly understood at the molecular level. Studies in recent funding period indicate that in the absence of any p53-like activity, made possible by mutations in the sole p53 family member in Drosophila, irradiated cells undergo robust apoptosis, thus providing the first genetic model to study IR-induced p53- independent apoptosis. p53-dependent and p53-independent apoptosis in Drosophila share common features such as the requirement for caspase activity and exacerbation by impaired DNA damage checkpoints or DNA repair. The key difference between p53-dependent apoptosis and p53-independent apoptosis is that net E2F activity appears to promote the former but inhibit the latter. To understand p53-independent apoptosis at the molecular level, a combination of genetic and cytological approaches will be used to identify and study genes and their products needed for this mode of cell death in Drosophila. The use of IR to eradicate tumors relies on its ability to induce cell death. Although p53- dependent apoptosis remains most widely studied, it is p53-independent apoptosis that is crucial for eliminating p53-deficient tumors, which constitute the majority of solid tumors. Experiments proposed will lead to a better understanding of p53-independent apoptosis in vivo in a multi-cellular context. Given the conservation of gene function between Drosophila and human, research proposed here has the potential to help us maximize the efficacy of radiation therapy of human cancers.